Suppressive function of androgen receptor in bone resorption
Suppressive function of androgen receptor in bone resorption
复制标题
DOI：
10.1073/pnas.1533500100
复制
发表时间：
2003-08-05
影响因子：
11.1
通讯作者：
Kato, S
中科院分区：
文献类型：
--
作者：
Kawano, H;Sato, T;Kato, S
由于睾丸睾酮局部转化的雌激素有助于雄激素的表观活性，雄激素受体(AR)在雄激素对骨骼组织的有益作用中的生理意义尚不清楚。我们在这里展示了使用Cre-loxP系统介导的基因靶向技术在小鼠中灭活AR会导致雄性而不是雌性的骨丢失。8周龄雄性AR基因敲除(ARKO)小鼠的组织形态计量学分析显示，骨转换高，骨吸收增加，导致骨小梁和皮质骨量减少，而不影响骨形状。可芳香化睾丸素治疗只能部分预防去睾丸的雄性Arko小鼠的骨质丢失。对ARKO小鼠原代成骨细胞和破骨细胞的分析表明，雄激素抑制成骨细胞的破骨生成支持活性需要AR功能，而对破骨细胞的抑制作用不是必需的。此外，在AR缺陷小鼠的成骨细胞中，编码主要破骨细胞诱导物的核因子-kappaB受体激活因子配体(RANKL)基因的表达被上调。我们的结果表明，AR功能在男性骨形成和重塑过程中是不可或缺的。
As locally converted estrogen from testicular testosterone contributes to apparent androgen activity, the physiological significance of androgen receptor (AR) function in the beneficial effects of androgens on skeletal tissues has remained unclear. We show here that inactivation of AR in mice using a Cre-loxP system-mediated gene-targeting technique caused bone loss in males but not in females. Histomorphometric analyses of 8-week-old male AR knockout (ARKO) mice showed high bone turnover with increased bone resorption that resulted in reduced trabecular and cortical bone mass without affecting bone shape. Bone loss in orchidectomized male ARKO mice was only partially prevented by treatment with aromatizable testosterone. Analysis of primary osteoblasts and osteoclasts from ARKO mice revealed that AR function was required for the suppressive effects of androgens on osteoclastogenesis supporting activity of osteoblasts but not on osteoclasts. Furthermore, expression of the receptor activator of NF-kappaB ligand (RANKL) gene, which encodes a major osteoclastogenesis inducer, was found to be up-regulated in osteoblasts from AR-deficient mice. Our results indicate that AR function is indispensable for male-type bone formation and remodeling.